Polymorphism and pseudopolymorphism (polymorphism of solvates and hydrates respectively) are phenomenons relating to the occurrence of different crystal forms for one molecule. There may be several different crystalline forms for the same molecule with distinct crystal structures and varying in physical properties like melting point, XRPD pattern and FTIR spectrum. These different crystalline forms are thus distinct solid forms which share the molecular formula of the compound from which the crystals are made up, however they may have distinct physical properties such as e.g. chemical stability, physical stability, hygroscopicity, solubility, dissolution rate, bioavailability, flowability, compressibility, pKa-value, residual solvent content, etc.
Ceftaroline fosamil, 4-[2-[[(6R,7R)-2-carboxy-7-[[(2Z)-2-(ethoxyimino)-2-[5-(phosphonoamino)-1,2,4-thiadiazol-3-yl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]thio]-4-thiazolyl]-1-methylpyridinium, is a prodrug with improved solubility compared to its active metabolite ceftaroline. Within the β-lectern antibiotics ceftaroline fosamil belongs to the subclass of cephalosporins and is indicated for the treatment of community-acquired bacterial pneumonia (CABP) as well as acute bacterial skin and skin structure infections. The product received marketing approval in the US (brand name Teflaro®) and is represented by the following formula (I):
EP1043327 A1 discloses amongst others ceftaroline fosamil per se in lyophilized non-crystalline form.
EP1310502 A1 discloses amongst others different crystalline forms of ceftaroline fosamil such as an acetic acid solvate monohydrate, a propionic acid solvate monohydrate and an acetonitrile solvate. Acetonitrile is a class 2 solvent and its content in pharmaceutical products is limited to 410 ppm (ICH Steering Committee, Guideline for Residual Solvents, 17.07.1997). Hence, the ceftaroline fosamil acetonitrile solvate disclosed in EP1310502 A1 is no suitable form for the preparation of a medicament as the acetonitrile amount of this crystalline form exceeds the limit significantly.
Both ceftaroline fosamil acetic acid solvate monohydrate and ceftaroline fosamil propionic acid solvate monohydrate of EP1310502 A1 contain carbon acids in their crystal structure. These carbon acids are partially replaced by water at increased relative humidities leading to a decreased carbon acid amount which finally affects the pKa of the drug substance and consequently the pH of the thereof prepared solution. Consequently in order to avoid batch-wise adjusting of the pH adjusting excipient, ceftaroline fosamil acetic acid solvate monohydrate and ceftaroline fosamil propionic acid solvate monohydrate of EP1310502 A1 need to be stored at low relative humidities in order to ensure a constant carbon acid amount and therefore a constant pKa value of the drug substance.
Ceftaroline fosamil is marketed as monoacetate monohydrate in form of a powder for reconstitution whereat the compound is blended with L-arginine as pH adjusting excipient in order to adjust a specific pH which is required for complete dissolution of the drug substance.